Transforming growth factor-beta (TGF-β), which is a family of 25-kDa dimeric proteins and has three members TGF-β1-3 in mammalian species, is a pleiotropic cytokine that regulates multiple biological processes, including extracellular matrix synthesis, cell proliferation, apoptosis and differentiation of many cell types and immune response. Many cell types synthesize and secrete TGF-β, and almost all of them express specific receptors for TGF-β.
The cell biological activities of TGF-β are well documented. TGF-β is a bifunctional growth regulator; it inhibits cell growth of most cell types including epithelial cells, endothelial cells and T cells but stimulates growth of mesenchymal cells such as fibroblasts and chondrocytes. The growth inhibitory activity of TGF-β toward T cells has been implicated in its immune suppression activity.
TGF-β plays a major role in wound healing. Genetic evidence from animal models of wound healing and evidence of TGF-β antagonist-induced promotion of normal wound healing in a standard pig and rabbit skin burn/excision injury models indicate that TGF-β produced at the injury site negatively regulates wound healing by inhibiting wound re-epithelization (or epithelial cell growth). Furthermore, TGF-β induces the deposition of extracellular matrix (ECM) proteins (e.g., collagen and fibronectin) by stimulating synthesis of ECM proteins, and inhibiting degradation of these ECM proteins. Because of this potent ECM deposition-stimulating activity, TGF-β is a major factor in fibrosis including: normal wound healing and scar formation, the formation of keloid, radiation-induced fibrosis, fibromatosis, hypertrophic burn scars, and fibrosis associated with autoimmune disorders such as scleroderma and sarcoidosis.
TGF-β is also an apoptosis inducer for certain cell types, including hair follicle cells and has been implicated in regulation of the hair cycle. The hair cycle is a highly regulated process which includes three phases, anagen (growing phase), catagen (regressing phase) and telogen (resting phase). TGF-β plays an essential part of catagen of the human hair by inducing apoptosis of follicle cells, which results in the initiation of the catagen phase. Male pattern baldness is the result of premature entry into catagen phase due to excess of androgen, which up-regulates TGF-β levels. TGF-β can also act either as an inflammatory or anti-inflammatory cytokine depending on tissue types. In skin injury, TGF-β acts as a proinflammatory agent by recruiting inflammatory cells to the injury site.
In view of the wide-ranging activities of TGF-β, it is clear that over-activity of TGF-β and negative regulation in normal physiology by TGF-β have been implicated in the conditions of fibrosis, normal wound healing, inflammation, and hair growth defects. Thus, compositions that inhibit the activity of TGF-β are extremely useful in treating those conditions associated with the over-activity of TGF-β and negative regulation in normal physiology by TGF-β.